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Abstract

Inflammatory bowel diseases are chronic gastrointestinal inflammatory disorders that affect millions of people worldwide. Genome-wide association studies have identified 200 inflammatory bowel disease-associated loci, but few have been conclusively resolved to specific functional variants. Here we report fine-mapping of 94 inflammatory bowel disease loci using high-density genotyping in 67,852 individuals. We pinpoint 18 associations to a single causal variant with greater than 95% certainty, and an additional 27 associations to a single variant with greater than 50% certainty. These 45 variants are significantly enriched for protein-coding changes (n = 13), direct disruption of transcription-factor binding sites (n = 3), and tissue-specific epigenetic marks (n = 10), with the last category showing enrichment in specific immune cells among associations stronger in Crohn’s disease and in gut mucosa among associations stronger in ulcerative colitis. The results of this study suggest that high-resolution fine-mapping in large samples can convert many discoveries from genome-wide association studies into statistically convincing causal variants, providing a powerful substrate for experimental elucidation of disease mechanisms.

Acknowledgements

We thank M. Khan and B. Wong for their assistance in designing illustrations, and K. de Lange for comments on the Supplementary Methods. We received support from the following grants. M.J.D. and R.J.X.: P30DK43351, U01DK062432, R01DK64869, Helmsley grant 2015PG-IBD001 and Crohn’s & Colitis Foundation of America. G.T., C.A.A. and J.C.B: Wellcome Trust grant 098051. M.G.: Fonds de la Recherche Scientifique-FNRS for the FRFS-WELBIO under grant no. WELBIO-CR-2012A-06 (CAUSIBD), BELSPO-IUAP-P7/43-BeMGI, Fédération Wallonie-Bruxelles (ARC IBD@Ulg), and Région Wallonne (CIBLES, FEDER). H.H.: ASHG/Charles J. Epstein Trainee Award. J.L.: Wellcome Trust 098759/Z/12/Z. D.M.: Olle Engkvist Foundation and Swedish Research Council (grants 2010-2976 and 2013-3862). R.K.W.: VIDI grant (016.136.308) from the Netherlands Organization for Scientific Research. J.D.R.: Canada Research Chair, National Institute of Diabetes and Digestive and Kidney Diseases grants DK064869 and DK062432, CIHR GPG-102170 from the Canadian Institutes of Health Research, GPH-129341 from Genome Canada and Génome Québec, and Crohn’s Colitis Canada. J.H.C.: DK062429, DK062422, DK092235, DK106593, and the Sanford J. Grossman Charitable Trust. R.H.D.: Inflammatory Bowel Disease Genetic Research Chair at the University of Pittsburgh, U01DK062420 and R01CA141743. E.D.: Marie-Curie Fellowship. A.-S.G: Fonds de la Recherche Scientifique-FNRS (F.R.S.-FNRS) and Fonds Léon Fredericq fellowships. J.H.: Örebro University Hospital Research Foundation and the Swedish Research Council (grant number 521 2011 2764). C.G.M. and M.P.: National Institute for Health Research (NIHR) Biomedical Research Centre awards to Guy’s & St Thomas’ NHS Trust/King’s College London and to Addenbrooke’s Hospital/University of Cambridge School of Clinical Medicine. D.E.: German Federal Ministry of Education and Research (SysInflame grant 01ZX1306A), DFG Excellence Cluster number 306 ‘Inflammation at Interfaces’. A.F.: Professor of Foundation for Experimental Medicine (Zurich, Switzerland). D.P.B.M.: DK062413, AI067068, U54DE023789-01, 305479 from the European Union, and The Leona M. and Harry B. Helmsley Charitable Trust. Additional acknowledgements for the original data are in the Supplementary Information.

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Supplementary information

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This file contains Supplementary Methods, Supplementary Notes, a Supplementary Box, the full list of members of the International Inflammatory Bowel Disease Genetics Consortium and acknowledgements for the original data.

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Editorial Summary

Fine-mapping IBD loci

Genome-wide association studies for inflammatory bowel disease (IBD) have identified over 200 associated loci but the causal variants at only several of these individual loci have been resolved. Here, Hailiang Hang and colleagues report fine-mapping of 94 of these IBD susceptibility loci using high-density genotyping in 67,852 individuals. They apply several new fine-mapping methods and identify 139 independent associations, 18 of which are resolved to a single causal variant with >95% certainty. This provides an example of how fine-mapping with high-density genotyping in large sample sizes is able to resolve causal variants at GWAS loci, an approach that may be used for other complex traits. To review the detailed fine-mapping results and annotations, a customizable browser is available at http://finemapping.broadinstitute.org.